Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Exploring the Relationship Between Clinical Presentation in Hallux Valgus and Response to AbobotulinumtoxinA Treatment.

The relationship between pain/disability and angular deviation of the hallux valgus (HV), and the impact of orthotic use, laterality, and pain variability on treatment outcomes remain unclear. This was explored in post hoc analyses of a placebo-controlled trial of abobotulinumtoxinA (aboBoNT-A; Dysport®) for HV-associated pain (NCT03569098). The primary endpoint was not met in this study (change from baseline Numeric Pain Rating Scale [NPRS] score vs placebo at week 8); however, there was a greater reduction from baseline in mean NPRS score at week 12 with aboBoNT-A 500U versus placebo (p = .06). Adults with painful HV without surgery were randomized (1:1:1) to aboBoNT-A 300U, aboBoNT-A 500U, or placebo. NPRS was completed for 7 days before baseline and weeks 4, 8, and 12. Over-the-counter orthoses were permitted. Participants (N = 186) had a mean [standard deviation, SD] age of 48.2 [13.1] years, 18% (33/186) used orthotics, and 67% (124/186) had bilateral HV. No associations between baseline pain severity and angular deviation were identified. Participants with high pain variability at baseline (SD > 2) had a poorer response to aboBoNT-A treatment than those with less variability. In conclusion, no relationship between HV-related pain/disability and angular deviation was observed. PLAIN LANGUAGE SUMMARY: A bunion (medical term: hallux valgus) is a common adult foot problem in which the big toe points inward toward the other toes, and this can be painful. How much the big toe points inward (how deformed the foot is) has been linked to the amount of pain the patient experiences. A better understanding of this foot deformity and bunion pain will help doctors and patients to make the right treatment decisions. A study was completed looking at how injections of a type of botulinum toxin (abobotulinumtoxinA) into specific muscles in the foot may help to reduce bunion pain in patients without surgery. This subsequent analysis of the study data looked at the amount of foot deformity in patients, the bunion pain they experienced, and which factors affected how well abobotulinumtoxinA worked to reduce bunion pain. The results of this study showed that the amount of foot deformity was not linked to the level of bunion pain. When deciding the best treatment option to relieve bunion pain, it is important that doctors not only consider how deformed the foot is, but also other important factors such as foot pain levels.

Pain Reduction With AbobotulinumtoxinA for the Treatment of Hallux Valgus in Adult Participants: Results of a Randomized and Placebo-Controlled Phase 2 Trial.

AbobotulinumtoxinA (aboBoNT-A, Dysport® [Ipsen, Paris, France]) inhibits acetylcholine release at the neuromuscular junction and may modulate pain signaling in hallux valgus (HV). This randomized study (NCT03569098) included a double-blind phase (aboBoNT-A 300U, 500U or placebo injections into forefoot muscles) and an open-label aboBoNT-A treatment period in participants with an HV diagnosis and no HV surgery. The primary endpoint was change from baseline in numeric pain rating scale (NPRS) score at week 8. Secondary endpoints included change in NPRS (other time points) and proportion of participants with ≥20% reduction from baseline NPRS (responders). Post-hoc analyses assessed number of days in a 7-day evaluation period that participants spent in a lower pain state than at baseline. Participants received aboBoNT-A 300U (n = 63), 500U (n = 60) or placebo (n = 63). Superiority to placebo was not observed with either aboBoNT-A dose at week 8, thus the primary endpoint was unmet. At week 12, a trend toward efficacy was observed with aboBoNT-A 500U versus placebo and the proportion of participants with ≥20% reduction from baseline NPRS was greater with aboBoNT-A 500U versus placebo (p = .006). Participants in the aboBoNT-A 500U group spent more days with lower NPRS than their lowest baseline score, and with NPRS ≥2 points lower than their mean baseline NPRS at weeks 8 and 12 versus placebo (all p < .05; post-hoc). AboBoNT-A was well tolerated. Although the primary endpoint was unmet, other endpoints showed a nominal advantage for aboBoNT versus placebo for treatment of HV-related pain, particularly at week 12. Further clinical evaluation is needed to establish whether botulinum toxins represent a viable non-operative treatment option for HV-associated pain. PLAIN LANGUAGE SUMMARY: Hallux valgus is the medical name for a bunion, a foot deformity that can worsen over time. Patients with bunions experience pain and walking can become difficult, which can affect their quality of life. Foot support aids (e.g., braces, splints and inserts) are available, but surgery is the standard treatment. This study looked at how injections of a specific type of botulinum toxin, called abobotulinumtoxinA or "aboBoNT-A", into the foot may help to reduce pain in patients with bunions. The study included 186 patients aged 18 to 75 years who had not had surgery on their bunion. The researchers looked at how well the injections worked using scales that measure the pain levels the patient experienced. The main outcome was whether patients who had aboBoNT-A injections had less pain after 8 weeks than they did before treatment. The study included patients who were injected with saltwater (no treatment) to check that any treatment effect was real. Researchers also looked at the results after 12 weeks, as well as how many patients had less pain after treatment than before and how many days in a given week patients experienced less pain after treatment than they did before. There was no reduction in pain levels with aboBoNT-A injections after 8 weeks compared with no treatment. However, the other study outcomes suggested that aboBoNT-A resulted in a small benefit compared with no treatment, especially after 12 weeks. Further medical research is needed to establish whether botulinum toxins represent an alternative treatment to surgery for the pain associated with bunions.

AbobotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity regardless of spinal cord injury or multiple sclerosis etiology: Pooled analysis of two phase III randomized studies (CONTENT1 and CONTENT2).

BACKGROUND: Neurogenic detrusor overactivity incontinence (NDOI) is often inadequately managed with oral therapy. OBJECTIVE: To assess efficacy and safety of abobotulinumtoxinA (aboBoNT-A; Dysport®; Ipsen Ltd.) according to etiology of NDOI. DESIGN, SETTING, AND PARTICIPANTS: Two phase III, randomized, double-blind studies (CONTENT1 [NCT02660138] conducted in Asia, Europe and North America; CONTENT2 [NCT02660359] conducted in the Americas, Asia, Europe and Oceania) both included patients with spinal cord injury (SCI) or multiple sclerosis (MS), with inadequately managed NDOI, regularly performing clean intermittent catheterization (CIC). INTERVENTION: Patients in CONTENT1 and CONTENT2 received aboBoNT-A injections 600 U (n = 162)/800 U (n = 161), or placebo (n = 162) into the detrusor muscle. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoint: mean change from baseline in number of NDOI episodes/week at Week 6. Secondary endpoints: proportion of patients with no NDOI episodes; incontinence-related quality of life (I-QoL); urodynamic parameters; and time-to-retreatment. Safety was also assessed. Statistical analyses were conducted for pooled populations by etiology (aboBoNT-A doses vs. placebo). RESULTS AND LIMITATIONS: Of 485 randomized patients, 341 (70%) and 144 (30%) had SCI and MS etiologies, respectively. A significant reduction was observed in mean NDOI episodes/week at Week 6 with both aboBoNT-A doses versus placebo in the SCI (all p < 0.001) and MS (all p < 0.01) groups, as well as significant improvements in I-QoL and urodynamic parameters. Median time-to-retreatment was longer in patients with MS (48-62 weeks across doses) than those with SCI (39-44 weeks). Safety data were similar between etiologies. Urinary tract infection was the most frequent adverse event; similar numbers were reported across treatment groups. CONCLUSIONS: AboBoNT-A was well tolerated and significantly improved continence and bladder function, and QoL, in patients with SCI or MS with NDOI performing regular CIC. PATIENT SUMMARY: AboBoNT-A injections improved QoL, symptoms, and bladder function in patients with SCI or MS with bladder muscle overactivity that causes incontinence.

Liquid AbobotulinumtoxinA: Pooled Data From Two Double-Blind, Randomized, Placebo-Controlled Phase III Studies of Glabellar Line Treatment.

BACKGROUND: AbobotulinumtoxinA (aboBoNT-A) solution is a new ready-to-use formulation developed to reduce preparation time and improve reproducibility of injections. OBJECTIVE: To further evaluate treatment of moderate-to-severe glabellar lines (GLs) using pooled data from 2 Phase III studies. METHODS: Following double-blind treatment with 50 U aboBoNT-A solution (n = 251) or placebo (n = 123), GL severity was assessed by investigators (ILA) and subjects (SSA). Other assessments included subject-reported time to onset, subject satisfaction, FACE-Q, and adverse events. RESULTS: One month after aboBoNT-A solution treatment, 88% had none-or-mild GLs at maximum frown and 93% had ≥1-grade improvement in ILA (similar for SSA), 24% to 27% remaining improved at Month 6. Glabellar lines responder rates remained higher than placebo throughout Month 6 ( p < .001). Almost two-thirds of subjects reported onset within 3 days, nearly a quarter reporting effect by Day 1. Subject satisfaction with GL appearance, and FACE-Q satisfaction with facial appearance overall and psychological well-being were also improved over placebo throughout Month 6, p < .05. Treatment-related adverse events were nonserious and mild or moderate. CONCLUSION: Pooled analysis confirmed a duration of effect on GLs of up to 6 months for aboBoNT-A solution, with onset starting within 24 hours, high subject satisfaction, and improved psychological well-being. The treatment was well tolerated.

Goal Attainment after Treatment with Abobotulinumtoxina and a Tailored Home Therapy Programme in Children with Upper Limb Spasticity: Descriptive, Exploratory Analysis of a Large Randomized, Controlled Study

OBJECTIVE: This exploratory analysis of a large, randomized, double-blind study (NCT02106351) describes the effect of treatment with abobotulinumtoxinA followed by a tailored home exercises therapy programme in enabling children with upper limb spasticity due to cerebral palsy to achieve their functional goals using goal attainment scaling (GAS). METHODS: Children with cerebral palsy and spasticity in ≥ 1 upper limb received up to 4 injection cycles of abobotulinumtoxinA (2 U/kg (cycle 1 only), 8U/kg and 16U/kg) into the elbow and wrist flexors and other upper limb muscles selected to support individual treatment goals. Children followed a home exercises therapy programme, which included stretches and exercises specifically chosen to facilitate goal achievement and engagement in activities. RESULTS: For cycle 1, most children had active function goals set as their primary goal (69.7% vs 19.2% passive function goals). GAS T- scores and goal responder rates at week 16 indicated that most types of primary goal were achieved at least as expected during cycle 1 (all groups). Primary goal GAS T-scores were generally maintained for the first 3 abobotulinumtoxinA treatment cycles. CONCLUSION: Most children with upper limb spasticity treated with repeat cycles of abobotulinumtoxinA supported by an individualized home exercises therapy programme achieved their functional goals.

Efficacy and Safety of AbobotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity Incontinence Performing Regular Clean Intermittent Catheterization: Pooled Results from Two Phase 3 Randomized Studies (CONTENT1 and CONTENT2).

BACKGROUND: For patients with neurogenic detrusor overactivity incontinence (NDOI), treatment with oral medications is often unsatisfactory. OBJECTIVE: To assess the efficacy and safety of abobotulinumtoxinA (aboBoNT-A) for NDOI. DESIGN, SETTING, AND PARTICIPANTS: Two randomized, double-blind phase 3 studies (CONTENT1, NCT02660138; CONTENT2, NCT02660359) enrolled patients with NDOI who were regularly performing clean intermittent catheterization (CIC) and were inadequately managed with oral therapy. Pooled results from the first placebo-controlled treatment cycle are reported. INTERVENTION: Patients received injections of aboBoNT-A 600 U (n = 162) or 800 U (n = 161) or placebo (n = 162) into the detrusor muscle. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the mean change from baseline in NDOI episodes per week at week 6. Secondary endpoints reported are the proportion of patients with no NDOI episodes, the volume per void, urodynamic parameters, and quality of life (QoL). Safety was also assessed. Statistical analyses were conducted for the pooled study populations (each aboBoNT-A dose vs placebo). RESULTS AND LIMITATIONS: At week 6, NDOI episodes per week were significantly reduced in each aboBoNT-A group versus placebo (both p < 0.001) and the volume per void had significantly increased. Approximately one-third of patients in each aboBoNT-A dose group reported no NDOI episodes versus 3% of patients in the placebo group. Reductions in urinary incontinence (UI) were reflected in significantly greater improvements in UI-related QoL in the aboBoNT-A groups versus placebo. Urodynamic parameters (bladder capacity and detrusor pressure) were significantly improved with each aboBoNT-A dose versus placebo. Each aboBoNT-A dose was well tolerated. Symptomatic urinary tract infection was the most frequent treatment-emergent adverse event, with incidence comparable across the aboBoNT-A and placebo groups. The studies were terminated prematurely owing to slow recruitment and were not designed for statistical comparison between the two aboBoNT-A doses. CONCLUSIONS: Intradetrusor aboBoNT-A is an effective treatment and alternative option for patients with NDOI who have an inadequate response to oral anticholinergics and are already performing CIC. PATIENT SUMMARY: In patients with bladder muscle overactivity caused by neurological conditions (multiple sclerosis or spinal cord injury) and resulting in urinary incontinence, abobotulinumtoxinA injections improved their symptoms and bladder function, with no unexpected effects.

Long-term Efficacy and Safety of Liquid AbobotulinumtoxinA Formulation for Moderate-to-Severe Glabellar Lines: A Phase III, Double-Blind, Randomized, Placebo-Controlled and Open-Label Study.

BACKGROUND: A ready-to-use liquid formulation of abobotulinumtoxinA (aboBoNT-A solution) has been developed. OBJECTIVES: The aim of this study was to assess the long-term efficacy and safety of aboBoNT-A solution for the treatment of glabellar lines. METHODS: This was a multicenter, multinational, Phase III study (NCT02493946), with randomized double-blind placebo-controlled (DBPC; 2:1 aboBoNT-A solution 50 U/placebo) and open-label (4 cycles aboBoNT-A solution) periods; additional patients were recruited into the open-label period. Patients were 18 to 65 years old, BoNT-naïve, and dissatisfied/very dissatisfied with moderate/severe glabellar lines at maximum frown. Investigator's live assessment (primary endpoint)/subject's self-assessment of glabellar line severity at maximum frown, patient satisfaction with glabellar line appearance, and FACE-Q patient-reported scales (facial appearance overall, psychological well-being, aging) were assessed. Adverse events were monitored. Analyses were performed on DBPC and long-term analysis (LTA; all patients receiving ≥1 aboBoNT-A solution injection) populations. RESULTS: Responder rates for the investigator's live assessment, the subject's self-assessment, and patient satisfaction were consistent at Day 29 postinjection across repeat LTA cycles (82.2%-87.8%, 62.8%-80.6%, and 72.2%-87.8%, respectively), with statistically significantly higher responder rates vs placebo (DBPC cycle: 81.6% vs 0.8%, 68.1% vs 2.3%, and 83.1% vs 5.7%, respectively; all P < 0.0001). Consistent improvements on FACE-Q scales occurred with repeat cycles (DBPC cycle: aboBoNT-A solution vs placebo, P < 0.0001). No new or unexpected adverse events, or neutralizing antibodies, were observed. CONCLUSIONS: These results support the long-term efficacy and safety of aboBoNT-A solution, and its superiority over placebo, for treatment of glabellar lines in adults.

Significantly Increased Patient Satisfaction Following Liquid Formulation AbobotulinumtoxinA Treatment in Glabellar Lines: FACE-Q Outcomes From a Phase 3 Clinical Trial.

BACKGROUND: The FACE-Q patient-reported outcome assesses patient experiences/outcomes with aesthetic facial procedure. A recent trial of abobotulinumtoxinA (ASI, liquid formulation) was the first to our knowledge to assess satisfaction with FACE-Q after glabellar line (GL) injection. OBJECTIVES: The authors sought to evaluate patient satisfaction with ASI for GL treatment employing 3 FACE-Q scales: facial appearance, psychological well-being, and aging appearance. METHODS: This was a Phase 3, randomized, double-blind, placebo-controlled trial (NCT02353871) of ASI 50 units in adults with moderate-to-severe GL with 6-month follow-up. RESULTS: Significantly greater least squares mean changes from baseline were associated with ASI treatment (N = 125) vs placebo (N = 59) for satisfaction with facial appearance at all visits until day 148 (5 months; P < 0.0001-0.0037), psychological well-being at all visits (P < 0.0001-0.0279), and aging appearance at all visits except day 148 (P < 0.0001-0.0409). Significant differences (ASI vs placebo) were observed at all visits for individual items: "how rested your face looks" (P < 0.0001-0.0415), "I feel okay about myself" (P = 0.0011-0.0399), and "I feel attractive" (P < 0.0001-0.0102). Maximal least squares mean (standard error) changes in aging appearance score were -1.4 (0.3; ASI) and -0.3 (0.4; placebo). Investigators' live assessment of GL at maximum frown significantly correlated with improvements in FACE-Q facial appearance and psychological scales (all patients: r = -0.41 and r = -0.36 [both P < 0.0001], respectively). CONCLUSIONS: Significant improvements in patient satisfaction with aging, facial appearance, and, importantly, psychological well-being were demonstrated with ASI employing FACE-Q scales up to 5 to 6 months post-injection. Results support a long duration of efficacy with ASI and use of FACE-Q in future trials and clinical practice.

Liquid Formulation of AbobotulinumtoxinA: A 6-Month, Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of a Single Treatment, Ready-to-Use Toxin for Moderate-to-Severe Glabellar Lines.

BACKGROUND: Safety and efficacy of botulinum toxin A for glabellar line (GL) treatment are well established. Currently approved formulations require reconstitution before injection. OBJECTIVES: The authors sought to assess 6-month efficacy, safety, and patient satisfaction of new ready-to-use abobotulinumtoxinA solution for injection (ASI) in patients with moderate-to-severe GL at maximum frown. METHODS: The authors conducted a phase 3, double-blind, randomized, placebo-controlled trial (NCT02353871). Patients (N = 185) were randomized (2:1) to receive ASI 50 U or placebo. GL severity was evaluated at days 8, 15, 29, 57, 85, 113, 148, and 183 employing a 4-point scale for investigator's live assessment (ILA) and subject's self-assessment (SSA). Primary endpoint was ILA of GL at maximum frown at day 29, and secondary endpoints were ILA and SSA of GL at maximum frown (all time points), patient satisfaction with GL appearance, time to onset, and duration of action. RESULTS: Responder rates were significantly higher for ASI vs placebo (88.3% vs 1.4%; P < 0.0001) at day 29 by ILA and all time points by ILA (P < 0.0001-0.0441) and SSA (P < 0.0001-0.0036). Sixty percent of patients reported onset of treatment response on or before day 3 (P < 0.0001 vs placebo), and in 5% of patients, efficacy by ILA lasted 6 months (day 183; P = 0.0441 vs placebo). Patient satisfaction rates were significantly higher for ASI vs placebo at all visits (P < 0.0001). Safety was comparable with the known abobotulinumtoxinA profile. CONCLUSIONS: ASI was significantly efficacious for improving moderate or severe GL vs placebo by investigator and patient assessment. ASI was associated with high patient satisfaction, a long duration of action, and comparable safety profile to abobotulinumtoxinA.

Safety and pharmacodynamics of a novel recombinant botulinum toxin E (rBoNT-E): Results of a phase 1 study in healthy male subjects compared with abobotulinumtoxinA (Dysport®).

Naturally occurring botulinum toxin (BoNT) serotypes have different pharmacological features of therapeutic and aesthetic interest. This phase 1, double-blind, placebo-controlled study (EudraCT: 2016-002609-20) assessed safety, tolerability and pharmacodynamics (PD) of the first recombinant BoNT serotype E (rBoNT-E) versus abobotulinumtoxinA (Dysport®), administered to extensor digitorum brevis (EDB) of healthy males. Subjects were randomised 3:1 (n = 28) to single ascending rBoNT-E (0.04-3.6 ng) doses or placebo. A further 24 subjects received abobotulinumtoxinA (20, 40, or 70 U) or placebo. PD were assessed using compound muscle action potential (CMAP) amplitude. Demographics were similar between groups. All rBoNT-E doses were well tolerated (no severe treatment-emergent adverse events [TEAEs], serious adverse events, or treatment-related toxicities). Most TEAEs were mild/moderate and treatment-unrelated. rBoNT-E had a faster onset of action (days 1-2 post-injection), greater peak effect (>90% CMAP inhibition), and shorter duration of effect at highest tested doses versus abobotulinumtoxinA (onset of action ≤7 days post-injection; 70% maximal CMAP inhibition). rBoNT-E duration of effect was 2-7 weeks versus >26 weeks for abobotulinumtoxinA. Dose-dependent effects were observed for magnitude and duration of EDB CMAP inhibition, plateauing at 0.9 and 3.6 ng. rBoNT-E demonstrated a good safety profile and a PD profile that may address unmet therapeutic and aesthetic patient needs.

AbobotulinumtoxinA Efficacy and Safety in Children With Equinus Foot Previously Treated With Botulinum Toxin.

BACKGROUND: The effects of botulinum toxin are transient, and repeat injections are required in children with lower-limb spasticity. However, the efficacy of botulinum toxin in patients who have received previous injections has remained largely unexplored. METHODS: We present subgroup analyses of a phase III study conducted in ambulatory children (aged two to 17) with spastic equinus foot. Patients were randomized to single doses of abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injected into the gastrocnemius-soleus complex (one or both legs). The first analysis was prespecified to review the effect of abobotulinumtoxinA in children previously treated with botulinum toxin versus those children new to the treatment; a second post hoc analysis evaluated the effect of abobotulinumtoxinA in children who changed botulinum toxin formulation. RESULTS: Of the 241 randomized patients, 113 had previously received botulinum toxin, including 86 who had been treated with another formulation. In both analyses, muscle tone (Modified Ashworth Scale) and the Physicians Global Assessment, at week 4, improved with abobotulinumtoxinA treatment versus placebo, regardless of baseline botulinum toxin status. Placebo responses in patients new to treatment were consistently higher than in the previously treated group. CONCLUSIONS: These results demonstrate similar abobotulinumtoxinA efficacy and safety profiles in children with spasticity who are new to botulinum toxin treatment and those children who were previously treated. The efficacy and safety of abobotulinumtoxinA treatment in these previously treated patients were comparable with the overall trial population, indicating that doses of 10 and 15 U/kg/leg are suitable starting doses for children with spasticity regardless of the previous botulinum toxin preparation used.

Dose-Dependent Effects of AbobotulinumtoxinA (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study.

BACKGROUND: AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence-based information on optimal dosing for clinical use is limited. OBJECTIVE: To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS. DESIGN: Secondary analysis of a phase 3 study (NCT01313299). SETTING: Multicenter, international, double-blind, placebo-controlled clinical trial. PARTICIPANTS: A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose). METHODS: The overall effects of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects. MAIN OUTCOME MEASURES: Angle of arrest (XV1) and angle of catch (XV3) were assessed with the Tardieu Scale, and active range of motion (XA). RESULTS: At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (XV1, XV3, XA) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in XV3 and XA, suggesting a dose-dependent effect. CONCLUSIONS: Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints. LEVEL OF EVIDENCE: I.

Liquid Formulation of AbobotulinumtoxinA Exhibits a Favorable Efficacy and Safety Profile in Moderate to Severe Glabellar Lines: A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trial.

BACKGROUND: In most countries, approved botulinum toxin type A formulations require reconstitution before injection. OBJECTIVES: To evaluate the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA (abobotulinumtoxinA solution for injection, ASI) in subjects with moderate to severe glabellar lines (GL). METHODS: In this Phase II, double-blind, placebo-controlled, randomized study, 176 female subjects (aged 30 to 60 years) were randomized into five treatment groups: ASI 20, 50, or 75 U, reconstituted abobotulinumtoxinA (aboBoNT-A) 50 U, and placebo. GL severity was assessed at maximum frown using a 4-point grading scale. Responders were subjects with severity grade of moderate [2] or severe [3] at baseline improving to none [0] or mild [1], evaluated at each time-point by Investigator's Live Assessment (ILA) or Subject's Self-Assessment (SSA). Safety profiles were also determined. RESULTS: Baseline characteristics were similar across groups. Responder rates on Day 29 by ILA were significantly greater for ASI 20, 50, and 75 U versus placebo (88.9%, 91.4%, and 87.9% vs. 0%, respectively; P < 0.0001). Similar results were observed by SSA. A greater proportion of responders was observed in ASI groups vs placebo from Day 8 to 113 for ILA and SSA (P < 0.001). AboBoNT-A responder rate on Day 29 for ILA was 77.1% (P < 0.1006 vs ASI 50 U); with comparable results by SSA. The ASI safety profile was comparable to that of aboBoNT-A. CONCLUSIONS: Ready-to-use liquid formulation of abobotulinumtoxinA was shown to be efficacious, with comparable results to reconstituted abobotulinumtoxinA, and to have a favorable safety profile in subjects with severe to moderate GL.

Progeny's mental aptitudes in man: relationship with parental age at conception and with some environmental factors.

Psychometric tests obtained from 6564 young men were studied as a function of the parents' ages at conception and of some characteristics of the subject's postnatal environment. Individual scores, from 0 to 20, were divided into two groups: n(1)11 and n(2)<11. In univariate analysis, scores <11 were respectively related to low height, high number of siblings and junior in birth order, subject's and parents' tobacco consumption, parents' alcohol consumption, subject's and parents' low academic standard, parents' youth or ageing at conception. In multivariate analysis, these scores remained related to low height, junior in birth order, subject's and parents' tobacco consumption, parents' low academic standard, parents' youth (both <20). Regarding the respective influences of the environment and of the subject's genome on his cerebral development, one can hypothesize a complementarity between these two factors through the possibility of a genetically determined individual synaptic potential, revealing itself, more or less, according to environmental conditions.

Frontal Assessment Battery is a marker of dorsolateral and medial frontal functions: A SPECT study in frontotemporal dementia.

The objective of this study is to identify the cerebral regions that are assessed by the Frontal Assessment Battery (FAB). Using SPM voxel-based analysis, we looked for correlations between FAB performance and brain SPECT perfusion in 47 patients with the frontal variant of frontotemporal dementia (fv-FTD) recruited by the French FTD research network, a multicentre initiative of French University hospitals with expertise in the field of dementia. A significant correlation was found between FAB performance and perfusion in the medial and dorsolateral frontal cortex bilaterally, independently of age, gender and MMSE. No correlations were observed with orbital frontal or parietal perfusion, in spite of the presence of hypoperfusion in these areas, or with perfusion of any other cortical or subcortical region. These findings confirm that the FAB is an adequate tool for assessing functions related to the dorsolateral and medial frontal cortex, and is thus useful for the evaluation of diseases associated with frontal dysfunction.

Importance of lack of interest in patients with mild cognitive impairment.

OBJECTIVE: Apathy is one of the most common behavioral symptoms in mild cognitive impairment (MCI). The aim of the authors' study was to examine the influence of the apathy dimensions, i.e., emotional blunting, lack of initiative, and lack of interest, on the risk of developing of Alzheimer disease (AD) in patients with MCI. DESIGN: Longitudinal study. SETTING: Fourteen French memory clinics. PARTICIPANTS: Apathy was assessed in 214 MCI patients. The main endpoint considered was the development of AD during the 3-year follow-up. MEASUREMENTS: The neuropsychiatric evaluation included the Goldberg anxiety scale and the Montgomery and Asberg Depression Rating Scale; apathy was assessed with the Apathy Inventory. RESULTS: After 3 years, 59 patients (27.2%) had developed AD. The risk of conversion to AD was significantly higher for patients with lack of interest. Using Cox analyses, controlling for age, gender and education, the difference between survival curves was significant for lack of interest. CONCLUSIONS: Lack of interest, a mild behavioral sign, could be an indicator of potential decline in MCI patients and underlines the importance of checking the cognitive status of these patients.